Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21])[CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:35][C:36]([C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1)=[O:37]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21])[CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH2:35][C:36]([C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)=[O:37])[CH2:17][CH2:18]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C(=O)CCl)cc1
Reactant: CC(C)C[C@H](C(N)=O)N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](C(N)=O)N(CC1CCN(CC(=O)c2ccc(C#N)cc2)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
To a solution of (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidin-4-ylmethyl)amino]-4-methyl-pentanoic acid amide (Example 126, 0.050 g, 0.12 mmol) and Et3N (0.040 mL, 0.30 mmol) in CH2Cl2 (2.0 mL) was added 4-(2-chloro-acetyl)-benzonitrile (55 mg, 0.30 mmol). The reaction was stirred at rt for 18 h and then was concentrated to residue. The residue was purified on a BIOTAGE® system (eluted with 80% EtOAc/hexanes) to produce 29 mg (48%) of the desired product as a white solid. MS (ESI), (M+H)+545.16; 1H NMR (CDCl3, 500 MHz) δ 7.72 (d, 2H, J=8.5), 7.50-7.65 (m, 2H), 7.50 (d, 2H, J=7.0), 7.35-7.45 (m, 2H), 6.67 (s, 1H), 5.32 (s, 1H), 4.14 (dd, 1H, J=5.0, 9.0), 3.52 (br s, 1H), 3.28 (t, 1H, J=14), 2.97 (dd, 1H, J=3.5, 14), 2.82 (br s, 1H), 1.00-2.00 (m, 10H), 0.71 (d, 3H, J=6.5), 0.66 (d, 3H, J=6.5).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[N:4]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C)C=O>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[O:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)=[CH:18][CH:17]=1
Reactant: Clc1ncccn1
Reactant: OCCOc1ccc(Cn2cccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc(OCCOc2ccc(Cn3cccn3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 96 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous N,N-dimethyl-formamide (5 ml) solution of 500 mg of 2-[4-(1-pyrazolyl)methylphenoxy]ethanol (produced in Reference Production Example 1 described below) under stirring over 10 minutes. After stirring at 60° to 70° C. for 2 hours, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 288 mg of 2-chloropyrimidine was added dropwise over 30 minutes. The mixture was then stirred at room temperature overnight and then at 60° to 70° C. for further 2 hours. The reaction mixture was poured into 50 ml of ice water, which was extracted with twice with 30 ml of toluene. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 339 mg of 4-(1-pyrazolyl)methyl-phenyl 2-(2-pyrimidyloxy)ethyl ether (compound 2). Yield, 50%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][CH2:21][O:22][C:23]1[N:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=1>>[CH:29]([OH:31])=[O:30].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[N:24][C:23]([O:22][CH2:21][F:20])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reactant: O=C(O)c1cnc(OCF)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCF)cn3)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) and 5-fluoromethoxy-pyrazine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as a light brown solid. MS (ISP): m/z=428.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reactant: CN1CCNCC1
Product: Cc1nc2ccc(N3CCN(C)CC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 73 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and N-methylpiperazine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 73%; MS: m/z=414 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCO>CN(C=O)C.[Cl-].[Na+].O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NS(C)(=O)=O)c2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
N-(5-fluoro-2-nitrophenyl)methanesulfonamide (1.33 g, 5.68 mmol) was dissolved in DMF (10 mL) and N-methylpiperazine (2.00 g, 20 mmol) was added. The reaction mixture was stirred at 20° C. for 1 h, and then heated with a heat gun for 5 min to reach boiling of DMF (150° C.), then left stirring for another hour. The reaction mixture was then poured into brine and extracted with toluene (10 mL×2), EtOAc (20 mL×2) and CH2Cl2 (20 mL×2), NaHCO3 was then added to the water phase and then the water phase was extracted with CH2Cl2 (20 mL×2). The organic phases were combined and dried (MgSO4) and concentrated to give a semi solid. EtOH was added and left over night and then filtered off to give 1.503 g (4.78 mmol) in 84% yield. MS (posES-FIA) m/z=found: 315; Calc M=314.10; Anal (C12H18N4O4S), C, H, N, S.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:11])[C:9]#[CH:10].[NH2:12][C:13]1[N:22]=[C:21]([C:23]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[C:20]2[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=2)[N:14]=1.C(Cl)Cl>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:12][C:13]1[N:22]=[C:21]([C:23]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:10]#[C:9][CH2:8][OH:11])[CH:19]=2)[N:14]=1
Reactant: C#CCO
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C#CCO)ccc2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3 ml of triethylamine, 368.7 μl of 2-propyn-1-ol, 36.6 mg of copper(I) iodide and 67.5 mg of bis(triphenylphosphine)palladium(II) chloride (15.2% of palladium) are added to a solution of 2 g of 2-amino-6-iodo-4-(1,3-dihydroisoindol-2-ylcarbonyl)quinazoline in 3 ml of DMF under argon. The mixture is stirred at room temperature for 48 h, 100 ml of DCM are added, and the mixture is subjected to aqueous extraction a number of times. The organic phase was dried and evaporated to dryness under reduced pressure in a rotary evaporator. A little ACN is added to the residue obtained, during which a yellow solid precipitates out. Filtration and drying (drying cabinet at 40° C.) gives 1.3 g of “A964”;
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1.[CH3:50][N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:54]3[CH2:55][CH2:56][CH2:57][N:51]([CH3:50])[CH2:52][CH2:53]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)c1
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(CN4CCCN(C)CC4)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.034 g, 0.05 mmol), 1-methylhexahydro-1H-1,4-diazepine (0.0069 g, 0.06 mmol), and acetic acid (0.0036 g, 0.06 mmol) were combined in 1,2-dichloroethane (2 mL). The reaction mixture was stirred for 30 min. Sodium triacetoxyborohydride (0.0148 g, 0.07 mmol) was added and the mixture stirred overnight at room temperature. Solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 2.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a white solid. LC-MS m/z 777.1 (M+H)+, 1.39 min (ret time); mp 105-107° C. Analytical HPLC shows 95.3% purity, (ret time 10.044 min).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[NH4+:23]>COCCOC>[NH2:23][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [NH4+]
Reactant: O=C(CCc1ccccc1)c1cccc(C(F)(F)F)c1F
Agent: [OH-]
Solvent: COCCOC
Product: Nc1c(C(=O)CCc2ccccc2)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 1-(2-fluoro-3-trifluoromethyl-phenyl)-3-phenyl-propan-1-one (4.8 g, 16.2 mmol) and ammonium hydroxide (150 ml of 30% solution) in DME (50 ml) was heated to 140° C. in a steel pressure reactor. After 3 hr, the reaction was cooled to 0° C., the steel pressure reactor was opened and the reaction was partitioned between water and EtOAc. The organic layer was dried (MgSO4) and concentrated to give 1-(2-amino-3-trifluoromethyl-phenyl)-3-phenyl-propan-1-one as a yellow oil (4.3 g). MS (ES) m/z 293.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16]Br>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:16][C:15]2[CH:18]=[CH:19][C:20]([F:21])=[C:13]([F:12])[CH:14]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CCOC(=O)c1cc[nH]c1C
Product: CCOC(=O)c1ccn(Cc2ccc(F)c(F)c2)c1C

Procedure:
Prepared in analogy to that of Example 5(a) from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3,4-difluorobenzyl bromide. The title compound, ESI MS (m/z): 280 (M+H)+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:15]=1[C:16]([OH:18])=O.C1CCN2C(=NCCC2)CC1.C[Si]([CH:39](C([O-])=O)[C:40]([O:42][CH2:43][CH3:44])=[O:41])(C)C>C1COCC1.C(#N)C>[F:13][C:14]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:15]=1[C:16](=[O:18])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)C(C(=O)[O-])[Si](C)(C)C
Reactant: O=C(O)c1cc(I)ccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
Employing the method utilized by Wang (Wang, X., Monte, W. T., Napier, J. J., Ghannam, A. Tetrahedron. Lett. 1994, 35, 9323), 1,1′-carbonyldiimidazole (1.82 g) in THF (20 mL) at 0° C. is treated with 2-fluoro-5-iodobenzoic acid (2.66 g) prepared according to literature procedures (Blackburn, B. K., Lee, A., Baier, M., Kohl, B., Olivero, A. G., Matamoros, R., Robarge, K. D., McDowell, R. S. J. Med Chem. 1997, 40, 717-729.) in portions over a 10 minute period. The mixture is stirred for 1 h and then allowed to warm to room temperature for an additional 1 h. The solution is then added dropwise into an enolate solution of ethyl trimethylsilymalonate at 5° C. prepared by the addition of DBU (3.35 g) to a solution of ethyl trimethylsilylmalonate (2.25 g) in acetonitrile (20 mL) at 5° C. with stirring for 45 minutes. The reaction mixture is allowed to warm to room temperature and stirred overnight. The orange solution is quenched with 100 mL of aqueous 10% citric acid solution and extracted with ethyl acetate. The organic extract is washed with aqueous 10% sodium bicarbonate solution and water, dried (Na2SO4), and concentrated in vacuo to give 2.4 g of the title compound as a yellow liquid. Physical characteristics: tlc Rf=0.66 (silica gel G; 20% EtOAc/hexane, visualize with I2).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=12.Cl[Si:33]([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:21]([Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:22][C:15]=12
Reactant: C[Si](C)(C)Cl
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of N,N-diisopropylamine (3.6 mmol) in THF (9 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of n-BuLi (2.5M in hexanes, 3.3 mmol) was added dropwise over 3 minutes. After 30 minutes of stirring, a solution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.1 mmol) in THF (9 ml) was added dropwise over 9 minutes. After an additional 2 hours of stirring at −78° C., chlorotrimethylsilane (3.1 mmol) was added dropwise over 1 minute. After 1 hour of stirring at −78° C., the reaction was quenched with saturated NH4Cl(aq) (10 ml), warmed to room temperature, and partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc and the organic layers combined, washed with brine, dried (MgSO4), concentrated, and purified by silica gel chromatography (isocratic CHCl3) to give the title product as a white solid (82%). ESMS [M+H]+: 410.8.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:11]=1[NH2:12].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.CCCCCCC.[Cu]>[Cl:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:11]=1[NH:12][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Nc1c(F)cc(F)cc1Cl
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: Cc1ccccc1C
Product: Cc1ccc(Nc2c(F)cc(F)cc2Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-iodotoluene (210 g, 0.96 mol), 2-chloro-4,6-difluoroaniline (204 g, 1.25 mol), copper powder (36 g, 0.57 mol), cuprous iodide (130 g, 0.68 mol), and potassium carbonate (118 g, 0.86 mol) in 500 ml of xylene is stirred vigorously and heated to reflux in a flask fitted with a Dean-Stark trap for 26 hours. After cooling to room temperature, the solids are filtered off, and the filter cake is washed with 100 ml of xylene. The solvents are evaporated under reduced pressure to give an oil which is dissolved in a mixture of 50 g of silica gel in 750 ml of heptane. The solids are filtered off and the solvents are evaporated under reduced pressure to give N-(2′-chloro-4′,6′-difluorophenyl)-4-methylaniline as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:37][N:38]([CH3:45])[C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40].C(NC(C)C)(C)C.CN(C=O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:44]#[C:43][CH2:42][NH:41][C:39](=[O:40])[N:38]([CH3:45])[CH3:37])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reactant: C#CCNC(=O)N(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reaction time: 6 h
Yield: 65.7 %

Procedure:
4-[3-({4-[(5-Chloro-7-iodo-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]-1-methylpiperazin-2-one (250 mg, 0.40 mmol) and N,N-dimethyl-N′-prop-2-yn-1-ylurea (60 mg, 0.48 mmol) in ethyl acetate (8 ml) stirred at room temperature, under an atmosphere of nitrogen, and treated with bis(triphenylphosphine)palladium(II) dichloride (28 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamine (81 mg, 0.80 mmol). The reaction was stirred 6 hr then DMF (3 ml) added and reaction heated at 60° for 3 hr. A further 60 mg N,N-dimethyl-N′-prop-2-yn-1-ylurea was added and heating continued for 3 hr. The mixture was then evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated to an orange oil. This was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (164 mg, 66%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.99 (quintet, 2H), 2.54 (t, 2H), 2.66 (t, 2H), 2.81 (s, 9H), 3.00 (s, 2H), 3.28 (t, 2H), 3.93 (s, 3H), 4.10 (d, 2H), 4.20 (t, 2H), 6.14 (s, 2H), 6.82 (t, 1H), 7.07 (s, 1H), 7.23 (s(broad), 1H), 7.85 (s, 1H), 8.40 (s(br), 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 624/626.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:16][O:17][C:18](=[O:40])[C@H:19]([CH2:36][CH2:37][S:38][CH3:39])[NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C>[CH3:16][O:17][C:18](=[O:40])[C@H:19]([CH2:36][CH2:37][S:38][CH3:39])[NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:24][C:23]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: O=C(O)c1cccnc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Nicotinic acid (345 mg, 2.8 mmol) was suspended in 10 mL of dichloromethane and oxalyl chloride (2.8 mL of a 2.0 M soln in methylene chloride) was added by syringe followed by one drop of DMF. The reaction mixture was stirred at 25° C. for 2 hours and then was evaporated and azeotroped with toluene. The resulting acid chloride was then dissolved in dichloromethane and a solution of (4-amino-2-phenylbenzoyl)methionine methyl ester (669 mg, 1.87 mmol), prepared as in Example 192B, in 5 mL of dichloromethane was added followed by 4 mL of saturated aqeuous NaHCO3 and the reaction was stirred at 25° C. for 3 hours. The layers were separated and the organic layer was dried over Na2SO4, filtered and evaporated to give 830 mg (96%) of [4-(3-pyridylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester as an oil. 1H NMR (300 mHz, CDCl3) δ 9.2 (d, 1H), 8.76 (d, 1H), 8.42 (bs, 1H), 8.2 (dt, 1H), 7.72-7.65 (m, 2H), 7.6 (dd, 1H), 7.45-7.35 (m, 5H), 6.02 (bd, 1H), 4.65 (dq, 1H), 3.68 (s, 3H), 2.20 (t, 2H), 2.01 (s, 3H), 1.98-1.88 (m, 1H), 1.80-1.78 (m, 1H). CIMS 464 (M+H)+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([CH3:34])[CH:28]=4)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([C:35]([F:37])([F:38])[F:36])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)=[CH:28][C:29]=1[CH3:34]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(N)(=O)=O)c4)c3)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.4 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.17 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as an off-white solid (0.1 g, 55%). MS (ISP) 505.1, 507.1 [(M+H)+]; mp 234° C.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:14]([C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[OH:15])=[CH:7][N:6]=1
Reactant: COc1ccccc1C=O
Reactant: Clc1ncc(Br)c(Cl)n1
Product: COc1ccccc1C(O)c1cnc(Cl)nc1Cl
Yield: 77 %

Procedure:
The compound was prepared from 5-bromo-2,4-dichloropyrimidine (Aldrich) and 2-methoxybenzaldehyde (Aldrich) in 77% yield in an analogous manner as described in Example 1. 1H NMR (300 MHz, CDCl3) δ 8.75 (s,1 H), 7.34 (d.t. 1H, J=2 Hz, 8 Hz), 7.16 (d,d, 1H, J=1.8 Hz, 7.3 Hz ), 6.96 (d, 1H, J=7.3 Hz), 6.95 (d,1H, J=8 Hz), 1H), 3.85 (s, 3H), 3.148 (br. s, 1H).